Discoid Lupus Erythematosus

Etiology

Lupus erythematosus is an inflammatory connective tissue disease characterized by generalized autoimmunity, pathogenic autoantibodies, and immune complexes, attributable to loss of immune tolerance. For discoid lupus erythematosus without associated SLE (chronic discoid lupus erythematosus), the evidence does not show whether circulating inflammatory cells and autoantibodies are involved in the pathogenesis. Still, it is evident that the cutaneous inflammatory infiltrates are dominated by Th1, rather than Th17, cells, in contrast to SLE.[5][6]

Epidemiology

Lupus can occur in all age groups, but discoid lupus erythematosus occurs more frequently in women in their fourth and fifth decades of life. Approximately 25% of patients with SLE may develop typical discoid lesions at some point during their illness, and 1% to 5% of patients with discoid lupus may develop SLE.

Ethnicity is also a major risk factor for developing LE, and its effect in some populations is almost as strong as that of gender. SLE prevalence is 4-fold higher in African-American women than in White American women (4 in 1000 versus 1 in 1000). In addition, African Americans tend to develop the disease at an earlier age and have a higher mortality rate.[7][8]

Pathophysiology

The pathogenesis of cutaneous lupus erythematosus is multifactorial, with an interplay between genetic and environmental factors. Some contributing environmental factors include UV radiation, medications, cigarette smoking, and, possibly, viruses. The interaction among these multiple factors triggers an inflammatory cascade of cytokines, chemokines, and inflammatory cell responses. Genes previously associated with SLE, including TYK2, IRF5, and CTLA4, confer an increased risk of developing discoid lupus erythematosus.

An analysis of 405 patients by Bockle et al found that smoking is highly associated with discoid lupus erythematosus. Bockle et al hypothesized that smoking may play a pathogenic role in cutaneous lupus erythematosus variants, including discoid lupus erythematosus and tumid lupus, by inducing apoptosis, stimulating T-cell proliferation, and increasing photosensitivity. Another explanation is that smoking induces DNA damage, leading to the formation of DNA adducts and the production of double-stranded DNA antibodies. Keratinocytes may also contribute to lupus skin damage by increasing the apoptotic rate and the production of proinflammatory cytokines, such as interferon-alpha and interleukin-6 for SLE and interferon-lambda for discoid lupus erythematosus.[9][10]

Histopathology

The histopathologic findings in cutaneous lupus vary by subtype. Overlap is evident in the histologic findings across the various clinical phenotypes, particularly acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, and discoid lesions. In cutaneous lupus erythematosus, basal cell damage (also referred to as vacuolar degeneration, hydropic change, or interface dermatitis) and lymphohistiocytic inflammatory infiltrates are commonly observed. In discoid lupus lesions, periadnexal inflammation, follicular plugging, and hyperkeratosis are typically observed in addition to interface dermatitis.[11] Dermal mucinosis, along with a thickened basement membrane, is also frequently noted.

Direct immunofluorescence (DIF) is the examination of the skin for deposits of immunoreactants. DIF of lesional skin can be useful for establishing a diagnosis of cutaneous lupus erythematosus when routine histopathology is equivocal. DIF does not replace routine histologic staining as the method of choice for establishing a diagnosis. In active lesions of discoid lupus erythematosus, DIF of lesional skin is positive in most cases. Antibody deposition at the dermal-epidermal junction and around hair follicles is the most characteristic DIF finding in cutaneous lupus erythematosus. These deposits are typically granular and composed primarily of immunoglobulin G and immunoglobulin M.[12][13]

The lupus band test (LBT) is a diagnostic procedure used to detect immunoglobulin and complement deposits along the dermo-epidermal junction in patients with lupus erythematosus. LBT can help distinguish systemic lupus erythematosus from chronic lupus erythematosus because, in patients with SLE, the LBT is frequently positive in both uninvolved and involved skin. In contrast, in patients with cutaneous lupus erythematosus, only the involved skin is positive.[14][15] The LBT is positive on the lesional skin in 75% of patients. Ideal lesions for LBT for discoid lupus erythematosus are on the head and neck that have been present for at least a few months.

History and Physical

Discoid lupus erythematosus is the most common form of chronic cutaneous erythematosus and can occur as a localized form (80%) with lesions on the face, ears, and scalp or as disseminated discoid lupus erythematosus (20%) with lesions above and below the neck. The disseminated form of discoid lupus erythematosus, especially when involving the trunk, is associated with an increased risk of progression to SLE up to 28%.[16]

Discoid lesions rarely present below the neck without concurrent involvement above the neck. Occasionally, discoid lesions develop on mucosal surfaces, including the lips, nasal mucosa, conjunctivae, and genital mucosa.[5] Some patients with discoid lesions exhibit a photodistribution. Sun exposure appears to play a role in lesion development. However, patients can have discoid lesions on the sun-protected skin, and there is no clear association between sun exposure and their development.

The first morphological sign of discoid lupus erythematosus is a well-defined, annular erythematous patch or plaque of varying size, followed by follicular hyperkeratosis, which is adherent to the skin. By removing the adherent scale, follicle-sized keratotic spikes similar to carpet tacks can be observed (carpet tack sign).[17] The lesions slowly expand with active inflammation and hyperpigmentation at the periphery, leaving depressed central atrophy, scarring, telangiectasia, and hypopigmentation.[18] Discoid lupus erythematosus can progress to irreversible scarring alopecia on the scalp. Although uncommon, a squamous cell carcinoma can develop in a longstanding discoid lesion at 2% to 3% and is often associated with a poor prognosis.[19]

Patients who present with discoid lesions may have associated arthralgias, but, over time, only approximately 10% to 20% of these patients eventually meet the classification criteria for SLE. Hyperkeratotic, verrucous plaques are noted in hypertrophic discoid lupus erythematosus, a rare entity of discoid lupus erythematosus.[20] 

Evaluation

In evaluating discoid lupus erythematosus, the dermatologist should obtain a detailed history and perform a thorough cutaneous examination, looking for signs of systemic disease. The diagnosis of discoid lupus erythematosus is primarily based on clinical features, although histological examination may be necessary to confirm the diagnosis.[21][22]

The initial step in diagnosis involves an antinuclear antibody titer, which is highly sensitive (95%-100%) but not specific. Autoantibodies to SSA/Ro, SSB/La, U1RNP, histones, and ssDNA are common in patients with SLE but are not disease-specific. No other specific autoantibodies are routinely used in practice to differentiate the subtypes of cutaneous lupus erythematosus. A further possible target of auto-antibodies is annexin 1, which has been suggested to play a crucial role in preventing autoimmune diseases. A recent study found a significantly higher level of anti-annexin 1 antibodies in patients with discoid lupus erythematosus, suggesting that anti-annexin 1 antibodies may be a new diagnostic marker for discoid lupus erythematosus. Anti-annexin 1 antibody levels in the serum did not correlate with disease activity.[23]

Treatment / Management

Early treatment of discoid lupus erythematosus lesions may result in complete clearance, whereas treatment failure results in permanent scarring. Hair loss, depressed scars, and pigmentary changes are often disfiguring, particularly in darker-skinned people. Some general measures, such as sun avoidance, avoidance of photosensitizing medications, and liberal application of sunscreen, are encouraged because cutaneous lesions are known to be exacerbated by sunlight.[24] Smoking cessation is encouraged, as smoking can increase discoid lupus erythematosus disease activity. Studies demonstrate a statistically significant decrease in the efficacy of antimalarial medication in individuals who have currently or ever smoked.[25][26][27]

Current first-line treatment for discoid lupus erythematosus consists of photoprotection in conjunction with topical or intralesional corticosteroids and topical calcineurin inhibitors.[28] Chronic discoid lupus erythematosus lesions that are not responsive to topical therapy or have a widespread disease involvement are candidates for systemic therapy. When discoid lupus erythematosus is refractory to these measures, other agents with varying degrees of proven efficacy are used. Currently, no medications have been approved specifically, and many of the drugs described in the literature were developed for use in other autoimmune disorders.(A1)

Acute exacerbations of discoid lupus erythematosus are treated with the application of a super-high or high-potency topical corticosteroid.[29] Clinical improvement is typically observed within 2 weeks of therapy. Treatment can be stopped when lesions are free of erythema or scale, indicating disease inactivity. Cutaneous atrophy is the major adverse effect associated with chronic use of topical corticosteroids. If lesions are refractory to high-potency topical corticosteroid use for 2 to 4 weeks, alternative therapy with intralesional corticosteroids or topical calcineurin inhibitors should be initiated. Topical calcineurin inhibitors such as tacrolimus 0.1% or 0.03% ointment and pimecrolimus 1% cream are most commonly used for facial lesions, as they do not cause atrophy.[30] However, these inhibitors are more expensive and have a slow onset of action. Clinical improvement is typically noted within 4 weeks of therapy. Low-potency topical corticosteroids or topical calcineurin inhibitors are typically used to maintain the discoid lupus erythematosus lesions in remission once the acute flare resolves.[31] Burning sensation after application that resolves within 1 to 2 weeks is the most common adverse effect of topical calcineurin inhibitors. Topical lesions that do not respond to the above therapy are treated with intralesional triamcinolone acetonide at a dose of 0.1 mL (3-5 mg/mL). Multiple injections into the lesion 1 cm apart should be given. Injections can be repeated every 3 to 4 weeks. If there is no clinical improvement after 2 to 3 injections, alternative treatment should be initiated. Common adverse effects of intralesional corticosteroids include dyspigmentation and skin atrophy.(A1)

Antimalarials are immunotherapeutic and are considered first-line systemic therapy for cutaneous lupus erythematosus. Hydroxychloroquine and chloroquine with or without quinacrine are currently used in the treatment of discoid lupus erythematosus. Hydroxychloroquine is preferred over chloroquine due to the lower risk of adverse effects, specifically retinal toxicity. Quinacrine is known to cause hematological abnormalities. Hydroxychloroquine is typically started at 200 mg/d and increased to 200 mg/d twice within 1 to 2 weeks if there are no adverse effects. The maximum dose of hydroxychloroquine should not exceed 5 mg/kg of real body weight per day, given its association with retinal toxicity.[32] Around 6 to 8 weeks of therapy are required to assess the effectiveness. Quinacrine at a dose of 100 mg/d is added to hydroxychloroquine if no clinical improvement is noted with hydroxychloroquine alone.[33] The chloroquine dose should not exceed 2.3 mg/kg of real body weight per day due to the risk of retinopathy.[32] Hydroxychloroquine and chloroquine should not be used together due to cumulative retinal toxicity. Patients should undergo baseline and periodic eye examinations during therapy. Blue-gray discoloration of the face, shins, and palate, and bleaching of light-colored hair may occur. Quinacrine use may lead to generalized yellow pigmentation of the skin, secretions, and sclera. (B2)

Other therapeutic options, such as retinoids, vitamin A analogs with anti-keratinizing and anti-inflammatory effects, are sometimes used in cutaneous lupus erythematosus, but documentation in the literature is limited. Topical retinoids such as tretinoin 0.05% cream or tazarotene 0.05% gel are used to treat hypertrophic discoid lupus erythematosus.[34] Topical retinoids are pregnancy category X drugs, and cutaneous irritation is a commonly observed adverse effect. Immunomodulators and Immunosuppressive agents such as methotrexate, systemic retinoids, dapsone, mycophenolate mofetil, azathioprine, intravenous immune globulin (IVIG), cyclophosphamide, and cyclosporine have also been used in the management of discoid lupus erythematosus. These therapies are generally considered second-line options for patients whose disease is refractory to first-line treatments.[35](B3)

Methotrexate at a dose range of 10 to 25 mg per week is used to treat discoid lupus erythematosus lesions. Clinical improvement is noted within 2 to 4 weeks of use, with the resolution of the lesions in about 6 to 8 weeks.[36] A dose of 5 to 10 mg of methotrexate is given as a test dose to assess if the patient can tolerate the drug. Liver function tests and a complete blood count are performed 5 to 6 days after drug administration to assess for adverse effects or intolerance to the medication. The most common adverse effects include gastrointestinal upset, hepatotoxicity, nephrotoxicity, teratogenicity, pulmonary fibrosis, bone marrow suppression, and oral ulcers. Daily folic acid supplementation may minimize gastrointestinal adverse effects.[37] Mycophenolate mofetil is administered in doses of 1 to 3 gm/d. Gastrointestinal upset, cytopenias, and teratogenicity are some of the adverse effects of mycophenolate mofetil.(A1)

Thalidomide, a potent teratogen, has been used in the treatment of discoid lupus erythematosus. In an early study of 60 patients receiving 50 to 100 mg per day, complete or marked regression was observed in 54 individuals (90%), with disease relapse in 71% of individuals with medication discontinuation.[38] Adverse effects apart from teratogenicity include drowsiness, constipation, rash, edema, xeroderma, peripheral neuropathy, and thromboembolism.[39] Lenalidomide is a thalidomide analog that may also prove useful in the treatment of discoid lupus erythematosus. Evidence suggests lenalidomide effectively treats discoid lupus erythematosus and has a less severe adverse effect profile than thalidomide, but may be similarly limited by a tendency to relapse once discontinued. IVIG is given at a 2 g/kg dose and repeated every 4 to 8 weeks.[40] IVIG is expensive, and cutaneous lupus erythematosus lesions tend to recur with its use. Adverse effects of IVIG therapy include headache, renal failure, hypersensitivity reactions, thrombosis, vasculitis, and aseptic meningitis.(A1)

Differential Diagnosis

Differential diagnoses of discoid lupus erythematosus include granuloma faciale, tinea faciei, cutaneous tuberculosis, cutaneous leishmaniasis, lymphoproliferative disorders, and sarcoidosis. Discoid lupus erythematosus–induced scarring alopecia can be confused with lichen planopilaris, tinea capitis, and central centrifugal cicatricial alopecia. Hypertrophic discoid lupus erythematosus may be confused with keratoacanthoma, squamous cell cancer, hypertrophic lichen planus, and prurigo nodularis.

Prognosis

Discoid lupus erythematosus lesions heal with scarring, atrophy, and dyspigmentation, causing more morbidity than mortality. Psychological functioning is affected by discoid lupus erythematosus lesions.[41] Exacerbations are associated with sun exposure and often occur in spring and summer. Localized discoid lupus erythematosus involving the scalp may lead to cicatricial alopecia. Generalized discoid lupus erythematosus is associated with the risk of progression to SLE in about 28%.[16] Chronic discoid lupus erythematosus lesions in about 2% to 3% can progress to squamous cell carcinoma, which is typically associated with a poor prognosis.[19] Early detection and treatment of discoid lupus erythematosus lesions can minimize the associated morbidity.

Complications

Complications associated with discoid lupus erythematosus and its progression to SLE include the following

• Cicatricial alopecia
• Pancytopenia
• Thromboembolism
• Arthritis
• Myositis
• Hypertension
• Renal failure
• Neuropsychiatric manifestations such as seizures and depression
• Pleuropericarditis
• Pancreatitis and mesenteric vasculitis
• Optic neuritis
• Therapy-related adverse effects
• Vitamin D deficiency 

Regular monitoring of discoid lupus erythematosus lesions and therapy-related adverse effects is crucial to prevent complications and promote clinical resolution.